Thiophene and thiazole substituted trifluoroethanone derivatives as histone deacetylase (HDAC) inhibitors

1. A compound of formula I:

wherein:

each of the (X═O) linked group and trifluoroacetyl group is independently substituted on any carbon ring atom;

A is CH;

D is CH;

X is C;

R 1 is hydrogen, C 1-6 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, a 5 membered heteroaromatic ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S, not more than one heteroatom of which is O or S, a 6 membered heteroaromatic ring containing 1, 2 or 3 nitrogen atoms, or a 7-10 membered saturated, partially saturated or unsaturated heterocyclic ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S; any of which rings being optionally substituted by one or more groups independently selected from halogen, cyano, C 1-6 alkyl, C 1-6 alkoxy, mercaptoC 1-6 alkyl, haloC 1-6 alkyl, haloC 1-6 alkoxy, amino, C 1-6 alkylamino and di(C 1-6 alkyl)amino; or

R 1 together with —(CH 2 ) b —N—(CR 2 R 3 ) a W forms a 4 membered saturated heterocycle containing one N atom or a 5, 6 or 7 membered saturated heterocycle containing one, two or three N atoms and zero or one O atom; the ring being optionally fused to a C 3-10 cycloalkyl ring, a 5, 6 or 7 membered saturated or partially saturated heterocyclic ring containing 1, 2 or 3 heteroatoms independently selected from N, O and S, a phenyl ring, a 5 membered heteroaromatic ring containing 1, 2 or 3 heteroatoms independently selected from N, O and S, not more than one heteroatom of which is O or S, or a 6 membered heteroaromatic ring containing 1, 2 or 3 nitrogen atoms; optionally substituted at a carbon ring atom by a 5 or 6 membered spiro ring containing zero, one or two heteroatoms independently selected from N, O or S which ring is optionally fused to a phenyl ring; or optionally bridged by one or two C 1-4 alkyl groups; any of which rings being optionally substituted by one or more groups independently selected from L-R 4 ;

each L is independently a direct bond, (CH 2 ) d or C═O;

R 2 and R 3 are independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, haloC 1-6 alkyl, C 6-10 aryl, a 5-membered heteroaromatic ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S, not more than one heteroatom of which is O or S; a 6 membered heteroaromatic ring containing 1, 2 or 3 nitrogen atoms; or a 7-10 membered unsaturated or partially saturated heterocyclic ring containing 1, 2 or 3 heteroatoms independently selected from N, O and S; or

R 2 and R 3 together with the carbon atom to which they are attached form a C 3-7 cycloalkyl group, >C═O or >C═CH;

W is halogen, C 1-6 alkyl, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, C 1-6 alkoxy, S(O) r (CH 2 ) c R 5 ; or a ring which is: C 3-5 cycloalkyl; a 5 or 6 membered saturated or partially saturated heterocyclic ring containing 1, 2 or 3 heteroatoms independently selected from N, O and S; a 6-13 membered saturated, partially saturated or unsaturated hydrocarbon ring; a 5 membered heteroaromatic ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S, not more than one heteroatom of which is O or S; a 6 membered heteroaromatic ring containing 1, 2 or 3 nitrogen atoms; or a 7-15 membered saturated, partially saturated or unsaturated heterocyclic ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S; any of which alkyl groups or rings being optionally substituted by one or more groups independently selected from R 6 ;

each R 4 is independently halogen; cyano; hydroxy; oxo; C 1-6 alkyl; haloC 1-6 alkyl; C 1-6 alkoxy; mercaptoC 1-6 alkyl; haloC 1-6 alkoxy; C 1-6 alkylcarbonyl; C 1-6 alkoxycarbonyl; nitro; N(R a ) 2 ; N(R a )CON(R a ) 2 ; N(R a )CO(C 1-6 alkyl); N(R a )CO 2 (C 1-6 alkyl); S(O) r (CH 2 ) c R 5 ; C 3-10 cycloalkyl; C 6-10 aryl; C 6-10 arylC 1-6 alkyl; C 6-10 aryloxyC 1-6 alkyl; C 6-10 arylcarbonyl; a 5 or 6 membered saturated or partially saturated heterocyclic ring containing 1, 2 or 3 heteroatoms independently selected from N, O and S; a 5 membered heteroaromatic ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S, not more than one heteroatom of which is O or S; a 6 membered heteroaromatic ring containing 1, 2 or 3 nitrogen atoms; or a 7-10 membered unsaturated or partially saturated heterocyclic ring containing 1, 2 or 3 heteroatoms independently selected from N, O and S; any of which alkyl groups or rings being optionally substituted by one or more groups independently selected from cyano, oxo, hydroxy, halogen, C 1-6 alkyl, C 1-6 alkoxy, mercaptoC 1-6 alkyl, haloC 1-6 alkyl, haloC 1-6 alkoxy, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, a 6 membered heteroaromatic ring containing 1, 2 or 3 nitrogen atoms and C 6-10 aryl, any of which rings being optionally substituted by one or more groups independently selected from halogen, C 1-6 alkyl, C 1-6 alkoxy and haloC 1-6 alkyl;

R 5 is C 1-6 alkyl, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, C 6-10 aryloxy, a 5 membered heteroaromatic ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S, not more than one heteroatom of which is O or S, a 6 membered heteroaromatic ring containing 1, 2 or 3 nitrogen atoms, or a 7-10 membered saturated, partially saturated or unsaturated heterocyclic ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S; any of which alkyl or alkenyl groups or rings being optionally substituted by one or more groups independently selected from halogen, cyano, oxo, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkyl, haloC 1-6 alkoxy, N(R a ) 2 , —C 1-6 alkylN(R a ) 2 , C 1-6 alkylcarbonyl, C 1-6 alkoxycarbonyl, C 6-10 aryl and C 6-10 aryloxy rings, the rings being optionally substituted by one, two or three groups independently selected from halogen, C 1-6 alkyl and haloC 1-6 alkyl;

each R 6 is independently halogen, cyano, oxo, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, mercaptoC 1-6 alkyl, haloC 1-6 alkyl, haloC 1-6 alkoxy, C 1-6 alkoxyC 1-6 alkyl, C 1-6 alkylcarbonyl; C 1-6 alkoxycarbonyl; nitro; N(R a ) 2 ; CON(R a ) 2 ; N(R a )CON(R a ) 2 ; N(R a )CO(C 1-6 alkyl); N(R a )CO 2 (C 1-6 alkyl); S(O) r (CH 2 ) c R 5 , O(C 1-10 alkyl)N(R a )COR 7 ; or a ring which is: C 3-7 cycloalkyl, C 6-10 aryl, C 6-10 arylC 1-6 alkyl, C 6-10 aryloxyC 1-6 alkyl, C 6-10 aryloxy, C 6-10 arylcarbonyl, a 5 or 6 membered saturated or partially saturated heterocyclic ring containing 1, 2 or 3 heteroatoms independently selected from N, O and S, or a 5 membered heteroaromatic ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S, not more than one heteroatom of which is O or S; any of which rings being optionally substituted by one or more groups independently selected from halogen, C 1-6 alkyl and C 1-6 alkoxy;

R 7 is C 1-6 alkoxy or C 1-6 alkyl optionally substituted by halogen or a 7-10 membered saturated or partially saturated heterocyclic ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S, the ring being optionally substituted by one or more groups independently selected from halogen, hydroxy, oxo, C 1-6 alkyl and C 1-6 alkoxy;

each R a is independently hydrogen, C 1-6 alkyl, C 1-6 alkylcarbonyl, C 1-6 alkoxycarbonyl, C 6-10 aryl or C 6-10 arylcarbonyl;

a is zero, one, two, three, four, five or six;

b is zero, one, two, three or four;

c is zero, one, two, three or four;

each d is independently one, two, three or four; and

r is zero, one or two;

or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 of formula IA:

wherein:

the trifluoroacetyl group is substituted on any carbon ring atom; and

a, b, A, D, R 1 , R 2 , R 3 , W and X are as defined in claim 1 ;

or a pharmaceutically acceptable salt thereof.

3. The compounds of claim 1 of formula IB:

wherein a, b, R 1 , R 2 , R 3 , W and X are as defined in claim 1 ;

or a pharmaceutically acceptable salt thereof.

4. The compound of claim 1 of formula IF:

wherein:

the trifluoroacetyl group is substituted on any carbon ring atom;

R 8 is hydrogen, C 1-4 alkyl, C 6-10 aryl, C 6-10 arylC 1-4 alkyl or C 3-7 cycloalkyl; and

a, A, D, X, R 2 , R 3 and W are as defined in claim 1 ;

or a pharmaceutically acceptable salt thereof.

5. The compound of claim 1 of formula IG:

wherein:

each of the (X═O) linked group and trifluoroacetyl group is independently substituted on any carbon ring atom;

e is 0, 1, 2 or 3;

Het is a 4 membered saturated heterocycle containing one N atom or a 5, 6 or 7 membered saturated heterocycle containing one, two or three N atoms and zero or one O atom; the ring being optionally fused to a C 3-10 cycloalkyl ring, a 5, 6 or 7 membered saturated or partially saturated heterocyclic ring containing 1, 2 or 3 heteroatoms independently selected from N, O and S, a phenyl ring, a 5 membered heteroaromatic ring containing 1, 2 or 3 heteroatoms independently selected from N, O and S, not more than one heteroatom of which is O or S, or a 6 membered heteroaromatic ring containing 1, 2 or 3 nitrogen atoms; optionally substituted at a carbon ring atom by a 5 or 6 membered spiro ring containing zero, one or two heteroatoms independently selected from N, O or S which ring is optionally fused to a phenyl ring; or optionally bridged by one or two C 1-4 alkyl groups; and

A, D, L, X and R 4 are as defined in claim 1 ;

or a pharmaceutically acceptable salt or tautomer thereof.

6. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.